U.S. Pat. No. 3,471,548 disclosed 4-amino-3-(p-chlorophenyl) butyric acid). 4-amino-3-(p-chlorophenyl) butyric acid) designates the R-isomers, the S-isomer and mixtures of R and S isomers including the racemate. Baclofen is indicated in many disease conditions such as for alleviating signs and symptoms of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus and muscular rigidity; in treatment of gastroparesis, non ulcer dydpepsia, gastroesophageal reflux diseases, for the treatment of depression or other psychological conditions, such as posttraumatic stress disorders, alcohol related disorders such as alcohol dependence is a chronic disorder that results from a variety of genetic, physiological and environmental factors, for promoting smoking cessation; for reducing addiction liability of narcotic agents; in the treatment of emesis; as an anti-tussive for the treatment of cough; in treating neuropathic pain and in treating musculoskeletal pain.
Clinical studies wherein baclofen is used for the treatment of spasticity have indicated that its major site of action is the spinal cord. Spasticity is one of the components of the upper motor neuron (UHM) syndrome but should not be considered in isolation when it comes to management strategies. Baclofen is used as a muscle relaxant and an anti-spastic agent for a variety of neurological disorders. It is a GABA-B receptor agonist that depresses the monosynaptic and polysynaptic excitation of mononeurons and interneurons. Currently, the most commonly used dosage form of racemic baclofen is the immediate release (IR) tablet (10-20 mg) to be administered three times a day. A serum concentration of 80 ng/ml or more is considered an effective concentration.
There is a wide inter-subject variation in the absorption and elimination of baclofen, but on an average it is rapidly and extensively absorbed after oral administration. Plasma elimination half-life of baclofen is approximately 3.5 hours (range 2 to 6 hours). Baclofen is excreted mainly by the kidneys in unchanged form although 15% is metabolized in the liver. Conventional baclofen therapy involves administration of 10 mg or 20 mg immediate release tablets three times a day. The dose ranges from 30 mg to 100 mg/day in divided doses. Baclofen is also available in the USA for chronic use as an injection to be administered by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture), and as implantable pumps approved by the Food and Drug Administration specifically for the administration of baclofen injection into the intrathecal space.
Frequent administration of immediate release baclofen tablets leads to fluctuations in plasma concentration producing peaks and troughs. Peaks in plasma concentration are associated with side effects, such as drowsiness (sedation), dizziness and muscle weakness and troughs cause inadequate control of muscle spasm. Side effects, like drowsiness and muscle weakness, are considered as major deterrents to the prescribers for up titration of the dosage for optimization of therapy. It is a matter of general concern, with conventional baclofen therapy, that the medication has to be administered frequently. Medication noncompliance among patients with medical illnesses has been reported to range from 15% to 85%. Although many factors are associated with medication non-compliance, it is thought that physicians can help promote compliance by prescribing medications that require a minimal number of doses.
A once-a-day or twice-a-day (b.i.d.) dosage formulation with the same therapeutic effectiveness as the conventional baclofen therapy could vastly improve patients' compliance with treatment. These will also improve the outcome of therapy, as a greater number of patients will adhere to treatment plan.
Although a single daily administration of the full daily dose (referred to as “high dose” to signify the higher amount of baclofen in a single sustained release tablet compared to that in one immediate release tablet even though the total daily dose remains the same) would be convenient however, the problem was that when baclofen was given in single high daily doses as sustained or controlled release preparation the bioavailability was reduced. This problem was studied by Merino et al (Proc. Eur. Congr. Biopharm. Pharmacokinet., 3rd (1987), 2, 564-73) and Biopharmaceutics and Drug Disposition (1989), 10(3), 279-97). The authors made significant conclusions about absorption of baclofen:                1. The lipophilicity of the drug at the actual pH values is negligible and therefore passive absorption mechanism for baclofen will be virtually inoperative and aqueous pore diffusion will be limited in view of the molecular weight of the drug. This limits the mechanisms by which baclofen can be absorbed to active or carrier mediated transport.        2. The absorption from the small intestine could occur due to the presence of a carrier mediated transport mechanism        3. No absorption could occur in the colon because of the absence of a carrier mediated transport mechanism.        4. Absorption of baclofen occurs by specialized transport mechanism which is saturable at higher concentrations and thus the use of high doses of baclofen is not recommended.        5. It can therefore be predicted that if controlled release formulations of baclofen are to be considered, they should be designed so that they would release most of the drug before reaching the illeo-caecal junction, i.e within no more than 8 hours.        
Further, it is known that gastric motility presents a significant resistance to preventing the passage of a dosage form into the colon for more than 8 hours. This resistance is due to the strong propulsive movements of the gut, particularly the occurrence of a periodic housekeeper wave that would sweep any physical object from the stomach into the intestine. (see Tmax in FIG. 1 and Table 7 when the systems were given in the fed state in the morning). The reasons for such shortfalls are suspected to lie in the nature of gastric motility and gastric emptying (See page 145 of E. A. Klausner et al, Journal of Controlled release 90 (2003), 143-162). The motor activity in the fed state is induced 5-10 min after ingestion of a meal and persists as long as food remains in the stomach, which may be from as short as about 2 hrs to as long as about 6 hrs, typically 3-4 hrs. In this period the contraction are of intermediate amplitudes. At the end of the fed phase, the motility pattern changes and goes into a fasted mode characterized by four periods of peristaltic activity over a 2 hr period. The aim of this activity is to clear the stomach and the small intestine of indigestible debris. It has four phases of which the third phase is known as the housekeeper phase characterized by very high amplitude contractions lasting for 5-15 minutes. Anything in the stomach is expected to be cleared due to these strong contractions or otherwise cause the problems of blocking of the pyloric sphincter or accumulation of the object in the stomach after it is repeatedly ingested by the human subject. It is also not possible to use a dosage form that would resist such housekeeper waves because it will be totally unacceptable for safety reasons to allow the accumulation of the residual dosage form in the stomach.
Nevertheless with the doubts whether a controlled drug delivery systems would provide adequate bioavailability, the present inventors proceeded to design and test a once-a-day controlled drug delivery system for baclofen to investigate possibilities of overcoming the drawbacks of poor absorption of baclofen in the lower parts of the intestine and obtain adequate bioavailability and a plasma profile with lower fluctuation in plasma levels. Two of such controlled drug delivery systems were disclosed in the pending patent applications US 20040180088 and US 20080107732. The bioavailability of baclofen from these controlled drug delivery systems containing 30 mg of baclofen was compared to the bioavailability of baclofen in the fed state (normal diet) from immediate release tablets (15 mg tablets given twice a day) in a comparative, open label, randomized two-way cross-over study in twelve healthy volunteers. It was found that the relative bioavailability of baclofen from the gastric retention controlled drug delivery system was 80% of the bioavailability from the immediate release tablets. These results were achieved by improving the design of prior known controlled drug delivery systems by incorporating features that cause the systems to expand in the gastric fluids and consequently be retained over longer periods in the stomach. However, this alone was not sufficient and an additional design feature in these systems was that they released a fraction of the drug in a more absorbable immediate release form that contributed to baclofen levels only for the initial duration of the 24 hr dosing nevertheless it obtained 24 hrs desired plasma levels by combining the more absorbable form with the slow release form which is criticized in the prior art as being “poorly absorbable”.
The inventors proceeded further to investigate whether this extent of absorption of baclofen from these once-a-day controlled drug delivery systems would also be obtained in patients suffering from spasticity and whether it was adequate to provide the desired efficacy over the duration of a day. It was surprisingly found that while the controlled release drug delivery demonstrated an efficacy equivalent to the immediate release baclofen tablets it also showed lower levels of sedation. Thus, a method of alleviating signs and symptoms of spasticity in human patient using once a day therapy was discovered for the first time. The method provided the benefit of reduced levels of sedation as compared to therapy with immediate release tablets and was claimed in US 20070265343 (European patent application EP 1849 462 A2 the contents of which are incorporated herein by reference). The EP 1849462 A2 claims a method of alleviating signs and symptoms of spasticity in human patient comprising orally administering to said human patients once in a day a controlled drug delivery system comprising an effective daily dose of baclofen or its pharmaceutically acceptable salt wherein said method is associated with reduced level of sedation in said patients as compared to conventional baclofen therapy with immediate release tablets administered three times a day on the same total daily dose. It further related to a method wherein the daily dose of baclofen or its pharmaceutically acceptable salt ranges from about 15 mg to about 80 mg. Particularly the method was useful when the daily dose of racemic baclofen was 30 mg or 45 mgs. The finding invention was surprising because instead of continuous treatment, in the sense of multiple daily dosing, with baclofen for patients suffering from spasticity which leads to the side effect of sedation, using an intermittent, in the sense of once a day, dosing amounting to the same overall daily dosage not only allows effective treatment of the underlying condition of spasticity but also reduces or eliminates the side effect of sedation. This was particularly surprising since the administration of a once a day formulation lead to higher plasma levels than the equivalent multiple dosing regimen and thus would ordinarily be expected to be associated with increased sedation as a side effect. Without wishing to be bound by theory, it is believed that the unexpected success of the formulations used arose as a consequence that they are retained in the stomach for longer than other systems. It was therefore an important benefit that the scope of industrial applicability and marketability of baclofen was increased because it could be used in a wider range of circumstances than previously possible when the risk of sedation might have precluded its use. Also, the invention could be particularly useful for treating patients who have a predisposition to suffering sedation as a side effect.